Increased vascular permeability or vascular leakage in the retina is an early and common feature of diabetic retinopathy and can result in diabetic macular edema. Vascular leakage is also responsible for cystoid macular edema (CME) secondary to cataract surgery, which is very common in diabetic patients. Overexpression of VEGF is a major causative factor leading to vascular leakage in diabetic retinopathy. Currently, there is no satisfactory treatment for macular edema, which remains a major cause of vision loss. Our recent studies have shown that several peptide angiogenic inhibitors, such as plasminogen kringle 5 (K5) and kallistatin, can reduce pathological vascular leakage in the retina. These peptides significantly decreased vascular leakage at doses much lower than that required for the inhibition of neovascularization. Furthermore, our preliminary data suggest that the K5-induced reduction of vascular leakage may be through blocking hypoxia-induced VEGF over-expression in the retina, while kallistatin reduces vascular leakage via blocking VEGF binding to its receptors. As diabetic macular edema is a multi-factorial and chronic disorder, we hypothesize that a sustained ocular delivery of a cocktail of multiple angiogenic inhibitors with different molecular targets may induce a long-term reduction of vascular leakage in diabetic retina. Our long-term goal is to develop a new treatment for CME and diabetic macular edema using peptide angiogenic inhibitors. [unreadable] [unreadable] In this Phase I project, we propose to prove two concepts: 1) the combination of two or more peptide angiogenic inhibitors with different molecular targets may have a synergistic effect on reduction of vascular leakage; 2) a sustained ocular delivery of angiogenic inhibitors may result in a long-term reduction of vascular leakage in the retina. We plan to use K5 and kallistatin as the first candidates for these studies, as they have displayed potent effects on vascular leakage when they were used alone, and they have different molecular mechanisms for their effects on vascular leakage. The synergistic effect on vascular leakage between K5 and kallistatin will be evaluated in a diabetic rat model. A sustained delivery system using slow-releasing peptide polymers will be developed. The pharmacokinetics of the peptides with different delivery routes will be compared. The long-term effect of the sustained delivery of K5 and kallistatin on vascular leakage will be evaluated in a diabetic animal model. This project is a necessary step in exploring the therapeutic and commercial potential of K5 and [unreadable] kallistatin as drugs for the treatment of diabetic macular edema. These studies will generate essential preclinical data for the development of a new treatment for diabetic macular edema using these peptides in Phase II. This new treatment will use natural human peptides and will be less invasive, compared to the current treatments. The slow releasing polymers and delivery techniques can be applied to other peptide drugs in the treatment of ocular disorders. [unreadable] [unreadable]